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Neuron. 2018 Nov 21;100(4):831-845.e7. doi: 10.1016/j.neuron.2018.09.027. Epub 2018 Oct 11.

Neonatal Tbr1 Dosage Controls Cortical Layer 6 Connectivity.

Author information

1
Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
3
Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
4
Department of Neurobiology, Physiology, and Behavior and Department of Psychiatry and Behavioral Sciences, Center for Neuroscience, University of California, Davis, Davis, CA 95618, USA.
5
Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
6
Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
7
Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
8
Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94143, USA.
9
Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: matthew.state@ucsf.edu.
10
Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Kavli Institute for Fundamental Neuroscience and Sloan-Swartz Center for Theoretical Neurobiology, University of California, San Francisco, San Francisco, CA 94143, USA.
11
Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: john.rubenstein@ucsf.edu.

Abstract

An understanding of how heterozygous loss-of-function mutations in autism spectrum disorder (ASD) risk genes, such as TBR1, contribute to ASD remains elusive. Conditional Tbr1 deletion during late mouse gestation in cortical layer 6 neurons (Tbr1layer6 mutants) provides novel insights into its function, including dendritic patterning, synaptogenesis, and cell-intrinsic physiology. These phenotypes occur in heterozygotes, providing insights into mechanisms that may underlie ASD pathophysiology. Restoring expression of Wnt7b largely rescues the synaptic deficit in Tbr1layer6 mutant neurons. Furthermore, Tbr1layer6 heterozygotes have increased anxiety-like behavior, a phenotype seen ASD. Integrating TBR1 chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) data from layer 6 neurons and activity of TBR1-bound candidate enhancers provides evidence for how TBR1 regulates layer 6 properties. Moreover, several putative TBR1 targets are ASD risk genes, placing TBR1 in a central position both for ASD risk and for regulating transcriptional circuits that control multiple steps in layer 6 development essential for the assembly of neural circuits.

KEYWORDS:

ASD; Tbr1; aggression; anxiety-like behavior; cortical development; development; layer 6; synapses

PMID:
30318412
PMCID:
PMC6250594
[Available on 2019-11-21]
DOI:
10.1016/j.neuron.2018.09.027

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